Signal transduction in pancreatic acinar cells, as well as in many other cell types, is believed to involve a cascade of events initiated by binding of a neurohormone to its cell surface receptors. According to the widely accepted model, receptor occupancy by an agonist results in phospholipase C activation, generation of inositol 1,4,5-trisphosphate (IP3), and release of Ca2+ from an intracellular non-mitochondrial IP3-sensitive Ca2+ storage pool. We have recently found that the CCK analog CCK-JMV180, which stimulates digestive enzyme secretion from rat acinar cells, causes intracellular Ca2+ concentrations ([Ca2+]) to rise but that CCK-JMV-180 does not cause IP3 generation. Furthermore, we have found that CCK-JMV-180 causes Ca2+ to be released from an IP3-insensitive intracellular storage pool. Preliminary studies indicate that CCK-JMV-180 causes the generation of a previously unrecognized water soluble messenger which can elicit Ca2+ release from an IP3-insensitive and caffeine/ryanodine-insensitive storage pool in permeabilized acinar cells. The current proposal will build upon these observations by (a) isolating and characterizing the messenger generated in response to CCK- JMV-180 stimulation; (b) characterizing the IP3-insensitive pool which releases Ca2+ in response to CCK-JMV-180 stimulation, and (c) defining the relationship between digestive enzyme secretion and the various receptor mediated events stimulated by either CCK-JMV-180 or caerulein. In rat pancreatic acini, both caerulein (a CCK Analog) and CCK-JMV-180 stimulate digestive enzyme secretion. High concentrations of caerulein, but not CCK-JMV-180, inhibit digestive enzyme secretion. Thus, the events which occur subsequent to CCK-IMV-180 stimulation may be intimately involved in stimulussecretion coupling in pancreatic acinar cells and the messenger generated in response to CCK-JMV-180 stimulation as well as the IP3-insensitive Ca2+ pool released by that messenger may be physiologically important. The current proposal is based on the hypothesis that the signal transduction system triggered in response to CCK-JMV-180 may be as important or even more important to stimulus-secretion coupling in the exocrine pancreas than the IP3-Ca2+ release system which has previously been described. Thus, the proposed studies may provide important insights into the physiological regulation of pancreatic acinar cell secretion.